Influence of MDR1 Genotype on Indinavir and Saquinavir Pharmacokinetics in Healthy Volunteers

Trial Information

Influence of MDR1 Genotype on Indinavir and Saquinavir Pharmacokinetics in Healthy Volunteers

The expression of P-glycoprotein, a transporter protein present in enterocytes as well as
other cells involved in the absorption and distribution of HIV protease inhibitors, has been
linked to a single nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T.
Individuals homozygous for the T allele have reduced P-gp expression compared to CC
individuals. Preliminary studies by other investigators to determine the influence of MDR1
genotype on HIV protease inhibitor pharmacokinetics have yielded inconclusive results. The
primary purpose of this study is to determine the relationship, if any, between MDR1
genotypes and plasma concentrations of the HIV protease inhibitors indinavir and saquinavir.
Secondary objectives of this investigation will (1) assess the relationship between CYP3A4
activity and indinavir and saquinavir exposure and (2) characterize the relationship, if
any, between P-gp expression on lymphocyte surfaces and MDR1 genotype. Up to 150 subjects
will be screened to enroll a total of 63 healthy volunteers (21 subjects each in the CC, TT,
and CT groups). Each subject will have blood drawn for P-gp expression analysis and MDR1
genotyping at screening. Next, subjects will receive oral midazolam 8 mg for CYP3A4
phenotyping; a single blood sample will be collected 4 hours after midazolam administration
for determination of midazolam and 1-hydroxymidazolam. Between 7 and 28 days after midazolam
administration, subjects will receive indinavir 800 mg every 8 hours for one day and a
single 800 mg dose the next morning (dose #4). Between 7 and 28 days after indinavir
administration, subjects will receive saquinavir soft-gel capsules 1200 mg three times daily
for 3 days and a single dose on the morning of day 4 (dose # 10). Post-dose blood samples
will be collected over 8 hours following dose #4 of indinavir and dose #10 of saquinavir.
Indinavir and saquinavir pharmacokinetic parameters (primarily AUC and Cmax) will be
compared across MDR1 genotype groups using ANOVA with post-hoc testing. 1-hydroxymidazolam:
midazolam ratios will be correlated to indinavir and saquinavir AUCs as well as compared
across MDR1 genotype groups. P-gp expression on lymphocyte surfaces will be determined by
flow cytometry, quantified, and compared across MDR1 genotype groups. Data from this
investigation will determine whether MDR1 genotype influences protease inhibitor plasma
concentrations.

Inclusion Criteria

- INCLUSION CRITERIA:

1. Males and females between the ages of 18 and 60 years.

2. Healthy by medical history and physical exam

3. Laboratory values within established guidelines for participation in clinical
studies: AST less than or equal to 2 times ULN (upper limit of normal); Serum
creatinine less than or equal to ULN; hemoglobin greater than or equal to 11
g/dL.

4. Ability to abstain from ingesting grapefruit or grapefruit juice 72 hours prior
to, and the days of midazolam phenotyping and indinavir and saquinavir
administration.

6. Females of child-bearing potential are able and willing to practice abstinence
or use other effective methods of birth control during Phase II of study that do
not include oral contraceptives.

EXCLUSION CRITERIA:

1. Concomitant routine therapy with any prescription, over the counter, herbal, or
holistic medications, including oral contraceptives for 30 days prior to study
participation.

- Subjects must be off oral contraceptives for at least 30 days prior to blood
collection for P-gp expression analysis; they must also be off oral
contraceptives for at least 30 days prior to midazolam phenotyping, and
indinavir and saquinavir administration.

- Intermittent (PRN) use of acetaminophen and non-steroidal anti-inflammatory
medications (i.e. ibuprofen) will be allowed during the study; these medications
should not be taken prior to, or within 4 hours of midazolam administration on
Day 0. These medications should not be taken during indinavir and saquinavir
administration until all blood samples for pharmacokinetic analyses of the
respective drugs have been obtained.

- Subjects will be allowed to take a multivitamin with minerals, or equivalent,
once daily if they desire to do so.

2. Inability to obtain venous access for sample collection.

3. Presence of Diabetes mellitus, Human immunodeficiency virus (HIV) infection, cardiac
disease (hypertension; congestive heart failure etc.), renal disease (chronic or
acute renal failure or insufficiency), respiratory disease (asthma requiring chronic
treatment; chronic obstructive pulmonary disease) or any other condition that may
interfere with the interpretation of the study results or not be in the best interest
of the subject in the opinion of the investigator.

4. Positive pregnancy test or breastfeeding female.

5. The presence of persistent diarrhea or malabsorption that would interfere with the
subject's ability to absorb drugs.

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